Functional Crosstalk between Type I and II Interferon through the Regulated Expression of STAT1

Daniel J Gough,Nicole L Messina,Ricky W Johnstone,Linda Hii,Paul J Hertzog,David E Levy,Christopher J P Clarke,Kanaga Sabapathy,Jodee A Gould,Ashley P S Robertson,Joseph A Trapani,Skip W Virgin

doi:10.1371/journal.pbio.1000361

Abstract

Author SummaryCells of the immune system release interferons (IFNs) in response to pathogens or tumor cells; these proteins signal to other immune cells to initiate the body's defense mechanisms. The two classes of IFNs—types I and II—have different receptors and distinct effects on the cells; however, there is “crosstalk” between them. In particular, small quantities of type I IFN can “prime” cells to produce a robust response to type II IFN. In this paper, we provide evidence to explain the molecular basis of this crosstalk. We show that continuous expression of the transcriptional activator c-Jun is responsible for producing basal, priming levels of a type I IFN; this signals to immune cells with the type I IFN receptor (IFNAR1) to maintain expression of STAT1 inside these cells. STAT1 is a key factor for immune cell responses to type II IFN. Thus, signaling by low levels of type I IFN primes the cells with sufficient STAT1 to respond robustly to a subsequent type II IFN signal. This work provides an alternative explanation of the priming phenomenon to a previous proposal that the ligand-bound type I receptor, IFNAR1, acts as a component of the type II IFN receptor.

Highlights

Type I and type II interferons (IFNs) have distinct roles in immune responses, there is substantial overlap between the genes and cellular responses they regulate
We show that continuous expression of the transcriptional activator c-Jun is responsible for producing basal, priming levels of a type I IFN; this signals to immune cells with the type I IFN receptor (IFNAR1) to maintain expression of STAT1 inside these cells
STAT1 is a key factor for immune cell responses to type II IFN

Summary

Introduction

Type I and type II interferons (IFNs) have distinct roles in immune responses, there is substantial overlap between the genes and cellular responses they regulate. It has been known for some time that many cells secrete small priming quantities of type I IFNs that facilitate more potent responses to subsequent stimuli [1,2,3]. Cellular responses to CSF-1 or IFNc can be affected by neutralizing type I IFN antibodies or knockout of type I IFN-Receptors (IFNAR) [2,4,5]. As the majority of responses to type I and II IFNs require the expression of the STAT1 transcription factor [6], this is a possible point of crosstalk between them

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